Bottle-brush type coatings with entangled hydrophilic polymer

ABSTRACT

The invention relates to a process for coating a material surface comprising the steps of:  
     (a) providing an inorganic or organic bulk material having covalently bound to its surface initiator moieties for radical polymerization;  
     (b) graft polymerizing a hydrophilic ethylenically unsaturated macromonomer from the bulk material surface in the presence of a biocompatible hydrophilic polymer being devoid of polymerizable ethylenically unsaturated groups and thereby entrapping said hydrophilic polymer within the polymer matrix formed by the polymerization of the macromonomer.  
     Composite materials obtainable according to the process of the invention have desirable characteristics regarding adherence to the substrate, durability, hydrophilicity, wettability, biocompatibility and permeability and are thus useful for the manufacture of biomedical articles such as ophthalmic devices.

[0001] The present invention relates to a process for coating articles,wherein the coating comprises a polymer having desirable characteristicsregarding adherence to the substrate, durability, softness,hydrophilicity, lubricity, wettability, biocompatibility andpermeability. More particular, the present invention relates to aprocess for coating an article, such as a biomedical material orarticle, especially a contact lens including an extended-wear contactlens, wherein the coating is composed of at least two individualhydrophilic polymer components. One of those hydrophilic componentscomprises polymer chains which are covalently bound to the substrate,whereas the second hydrophilic polymer is not covalently bound neitherto the surface of the substrate nor to the polymer chains, but is beingentrapped with said polymer chains.

[0002] Processes for preparing hydrophilic polymeric coatings on an“inert” hydrophobic substrate have been disclosed in the prior art. Forexample, WO 99/57581 discloses to first of all providing the articlesurface with covalently bound photoinitiator molecules, coating themodified surface with a layer of a polymerizable macromonomer and thensubjecting it to a heat or radiation treatment whereby the macromonomeris graft polymerized thus forming the novel article surface. Thecovalent binding of the photoinitiator molecules to the article surfaceis created by first subjecting the article surface to a plasma treatmentthereby providing the surface with functional groups, and then reactingsaid functional groups with co-reactive groups of a functionalphotoinitiator.

[0003] Surprisingly, it now has been found that articles, particularlybiomedical devices such as contact lenses, with an even improvedwettability, water-retention ability and biocompatibility are obtainedby first of all providing the bulk material surface with covalentlybound photoinitiator molecules, followed by grafting a hydrophilicethylenically unsaturated macromonomer from the bulk material surface inthe presence of a biocompatible hydrophilic polymer being devoid ofpolymerizable ethylenically unsaturated groups and thereby entrappingsaid biocompatible hydrophilic polymer within the polymer matrix formedby the polymerization of the macromonomer.

[0004] By this process, the macromonomer forms “bottle-brush” typetethered “hairy” chains on the bulk material surface having entangled abiocompatible hydrophilic polymer thereby forming a kind ofsemi-interpenetrating network (s-IPN) with the polymer chains of themacro-monomer.

[0005] The present invention therefore in one aspect relates to aprocess for coating a material surface comprising the steps of:

[0006] (a) providing an inorganic or organic bulk material havingcovalently bound to its surface initiator moieties for radicalpolymerization;

[0007] (b) graft polymerizing a hydrophilic ethylenically unsaturatedmacromonomer from the bulk material surface in the presence of abiocompatible hydrophilic polymer being devoid of polymerizableethylenically unsaturated groups and thereby entrapping said hydrophilicpolymer within the polymer matrix formed by the polymerization of themacromonomer.

[0008] Suitable bulk materials to be coated according to the inventionare, for example, quartz, ceramics, glasses, silicate minerals, silicagels, metals, metal oxides, carbon materials such as graphite or glassycarbon, natural or synthetic organic polymers, or laminates, compositesor blends of said materials, in particular natural or synthetic organicpolymers or modified biopolymers which are known in large number. Someexamples of polymers are polyaddition and polycondensation polymers(polyurethanes, epoxy resins, polyethers, polyesters, polyamides andpolyimides); vinyl polymers (polyacrylates, polymethacrylates,polyacrylamides, polymethacrylamides, polystyrene, polyethylene andhalogenated derivatives thereof, polyvinyl acetate andpolyacrylonitrile); or elastomers (silicones, polybutadiene andpolyisoprene).

[0009] A preferred group of materials to be coated are those beingconventionally used for the manufacture of biomedical devices, e.g.contact lenses, in particular contact lenses for extended wear, whichare not hydrophilic per se. Such materials are known to the skilledartisan and may comprise for example polysiloxanes, perfluoroalkylpolyethers, fluorinated poly(meth)acrylates or equivalent fluorinatedpolymers derived e.g. from other polymerizable carboxylic acids,polyalkyl (meth)acrylates or equivalent alkylester polymers derived fromother polymerizable carboxylic acids, or fluorinated polyolefines, suchas fluorinated ethylene or propylene, for example tetrafluoroethylene,preferably in combination with specific dioxols, such asperfluoro-2,2-dimethyl-1,3-dioxol. Examples of suitable bulk materialsare e.g. lotrafilcon A, neofocon, pasifocon, telefocon, silafocon,fluorsilfocon, paflufocon, elastofilcon, fluorofocon or teflon AFmaterials, such as teflon AF 1600 or teflon AF 2400 which are copolymersof about 63 to 73 mol % of perfluoro-2,2-dimethyl-1,3-dioxol and about37 to 27 mol % of tetrafluoroethylene, or of about 80 to 90 mol % ofperfluoro-2,2-dimethyl-1,3-dioxol and about 20 to 10 mol % oftetrafluoroethylene.

[0010] Another group of preferred materials to be coated are amphiphilicsegmented copolymers comprising at least one hydrophobic segment and atleast one hydrophilic segment, which are linked through a bond or abridge member. Examples are silicone hydrogels, for example thosedisclosed in PCT applications WO 96/31792 and WO 97/49740.

[0011] A particular preferred group of materials to be coated comprisesorganic polymers selected from polyacrylates, polymethacrylates,polyacrylamides, poly(N,N-dimethylacrylamides), polymethacrylamides,polyvinyl acetates, polysiloxanes, perfluoroalkyl polyethers,fluorinated polyacrylates or -methacrylates and amphiphilic segmentedcopolymers comprising at least one hydrophobic segment, for example apolysiloxane or perfluoroalkyl polyether segment or a mixedpolysiloxane/perfluoroalkyl polyether segment, and at least onehydrophilic segment, for example a polyoxazoline,poly(2-hydroxyethylmethacrylate), polyacrylamide,poly(N,N-dimethylacrylamide), polyvinylpyrrolidone polyacrylic orpolymethacrylic acid segment or a copolymeric mixture of two or more ofthe underlying monomers.

[0012] The material to be coated may also be any blood-contactingmaterial conventionally used for the manufacture of renal dialysismembranes, blood storage bags, pacemaker leads or vascular grafts. Forexample, the material to be modified on its surface may be apolyurethane, polydimethylsiloxane, polytetrafluoroethylene,polyvinylchloride, Dacron™ or Silastic™ type polymer, or a compositemade therefrom.

[0013] The form of the material to be coated may vary within widelimits. Examples are particles, granules, capsules, fibres, tubes, filmsor membranes, preferably moldings of all kinds such as ophthalmicmoldings, for example intraocular lenses, artificial cornea or inparticular contact lenses.

[0014] The bonding of the photoinitiator moieties according to step (a)may be accomplished

[0015] (i) according to the methods described in WO 99/57581, where thesurface of the bulk material is first of all subjected to a plasmatreatment thereby introducing reactive groups at the surface of thesurface, followed by reaction of said reactive groups with an initiatormoiety bearing co-reactive functional groups, or

[0016] (ii) by reaction of certain hetero-bifunctional compounds at thesurface of the bulk material said compounds having a first highlyreactive functional group, which is able to react with the “inert” bulkmaterial surface, and a second functional group for further covalentattachment of the initiator moieties.

[0017] Said hetero-bifunctional compound is, for example, a compound offormula

[0018] wherein R₂₉ is C₁-C₄-alkyl, C₁-C₄-alkoxy, amino, hydroxy, sulfo,nitro, trifluoromethyl or halogen,

[0019] g is an integer from 0 to 2,

[0020] L₁ is a group, which functions as a triggerable precursor forcarbene or nitrene formation,

[0021] L₂ is amino, C₁-C₄-alkylamino, hydroxy, glycidyl, carboxy or aderivative thereof, isocyanato or isothiocyanato, or is a radical offormula

—[L₃]_(h)—(spacer)—L₂′  (1a)

[0022] wherein L₂′ is amino, C₁-C₄-alkylamino, hydroxy, carboxy or aderivative thereof, isocyanato, isothiocyanato, —O-glycidyl or—O—C(O)—(CH₂)_(h1)—X₂, wherein h1 is from 1 to 4 and X₂ is carboxy or aderivative thereof,

[0023] L₃ is —NH—, —NC₁—C₆-alkyl-, —O—, —C(O)O—, —C(O)NH—, —NHC(O)NH—,—NHC(O)O— or —OC(O)NH—;

[0024] (spacer) is linear or branched C₁-C₂₀₀-alkylene which may besubstituted by hydroxy and/or interrupted by —O— except for C₁-alkyl, oris C₃-C₈-cycloalkylene, C₃-C₈-cycloalkylene-C₁-C₆-alkylene,C₃-C₈-cycloalkylene-C₁-C₂-alkylene-C₃-C₈-cycloalkylene orC₁-C₆-alkylene-C₃-C₈-cycloalkylene-C₁-C₆-alkylene; and

[0025] h is the number 0 or 1.

[0026] L₁ in formula (1) is, for example, a group of formula

[0027] or

—N₃  (2b)

[0028] wherein R₃₀ is an electron-withdrawing substituent, for examplefluorinated C₁-C₆-alkyl, such as a radical —C₂F₅ or preferably a radical—CF₃.

[0029] R₂₉ is preferably C₁-C₄-alkoxy, nitro, C₁-C₄-alkyl, hydroxy,amino or sulfo. The variable g is, for example, 1 or preferably 0.

[0030] One group of suitable radicals of formula (1) are those whereinL₁ is a group

[0031] and g is 0. A further group of suitable radicals of formula (1)are those wherein L₁ is a group —N₃, and g is 1 or preferably 0.

[0032] Throughout the application the terms carboxy derivative, aderivative of carboxy and the like are to be understood as meaning, forexample, a lactone, a carboxylic acid anhydride, halide, amide or ester,for example —C(O)Cl, —C(O)NH₂, —C(O)C₁-C₆-alkyl, —C(O)-phenyl or inparticular an activated ester such as carboxy having been reacted withan activating agent, for example with N-hydroxy succinimide (NHS) orsulfo-N-hydroxy succinimide. A particularly preferred carboxy derivativeis an activated ester of formula

[0033] wherein Ka⁺ is a cation, for example Na⁺ or K⁺.

[0034] The term glycidyl means a radical

[0035] The bivalent radicals L₃ are always to be understood that theleft bond is directed to the phenyl ring and the right bond is directedto the (spacer) radical.

[0036] According to one preferred embodiment of the invention, L₂ isamino, isocyanato, isothiocyanato, carboxy or a derivative thereof, andin particular amino, isocyanato, carboxy, or an activated carboxylicacid ester as mentioned above.

[0037] L₃ in formula (1a) is preferably a bivalent group —O—, —NH—,—C(O)O—, —C(O)NH— or —NHC(O)NH—, and is most preferably a radical —NH—,—C(O)O— or —C(O)NH—. h is preferably the number 1.

[0038] (spacer) in formula (1a) is preferably linear or branched,optional hydroxy-substituted, C₁-C₂₄-alkylene or C₄-C₁₆₀-alkylene whichis interrupted by —O—, more preferably C₁-C,₆-alkylene orC₈-C₁₆₀-alkylene which is interrupted by —O— and most preferablyC₂-C₁₂-alkylene or —(alk′)—O—(CH₂CH₂O)₁₈₋₁₆₀—(alk′)—, wherein (alk′) is,for example, C₁-C₆-alkylene, preferably C₁-C₄-alkylene, more preferablyC₁-C₃-alkylene and in particular 1,2-ethylene. If (spacer) is acycloalkylene or mixed alkylene/cycloalkylene radical, the meanings andpreferences given below for R₃₃ apply.

[0039] L₂′ is preferably amino, isocyanato, carboxy, a carboxyderivative, or a radical —O—C(O)—(CH₂)₂—X₂, wherein X₂ is carboxy or aderivative thereof. Particularly preferred meanings of L₂′ are amino,carboxy and an activated carboxylic acid ester as mentioned above.

[0040] A further preferred embodiment of the invention relates to theuse of a compound of formula (1), wherein L₂ is a radical of formula(1a), L₃ is —NH—, —C(O)O— or—C(O)NH—, h is 1, (spacer) is linearC₂-C₁₂-alkylene or—(C₂-C₃-alkylene)—O—(CH₂CH₂O)₁₈₋₁₆₀—(C₂-C₃-alkylene)—, and L₂′ iscarboxy, a carboxy derivative or a radical —O—C(O)—(CH₂)₂—X₂, wherein X₂is carboxy or an activated carboxylic acid ester as mentioned above.

[0041] Preferably, L₁ is a group of formula

[0042] g is 0, and L₂ is carboxy, a carboxy derivative, or a radical offormula (1a) above, wherein the above-given meanings and preferencesapply.

[0043] According to another preferred embodiment, L₁ is a group —N₃, gis 1 or preferably 0, R₂₉ is methyl, methoxy, hydroxy or nitro, and L₂is amino, carboxy, a carboxy derivative, isocyanato, isothiocyanato or aradical of formula (1a) above, wherein the above-mentioned meanings andpreferences apply, in particular amino.

[0044] The compounds of formula (1) may be applied to the materialsurface according to processes known per se. For example, the bulkmaterial is immersed in a solution of a compound of formula (1), or alayer of a compound of formula (1) is first of all deposited on the bulkmaterial surface to be modified, for example, by dipping, spraying,printing, spreading, pouring, rolling, spin coating or vacuum vapordeposition, with dipping or spraying being preferred. Most preferably, asolution comprising one or more different compounds of the formula (1)is sprayed onto the bulk material surface, which may be dry orpreferably wet. The compound of formula (1) may be applied to thematerial surface in one cycle or in repeated cycles.

[0045] Suitable solvents useful as solvents of the compounds of formula(1) are, for example, water, C₁-C₄-alkanols such as methanol, ethanol oriso-propanol, nitrites such as acetonitrile, tetrahydrofuran (THF),aqueous solutions comprising an alkanol, THF or the like, ketones, forexample acetone or methylethyl ketone, and also hydrocarbons, forexample halogenated hydrocarbons such as methylene chloride orchloroform. The concentration of the compound of formula (1) in thespray solution depends on the specific compound used but is in generalin the range of from 0.1 to 100 g/l, preferably 0.5 to 50 g/l, morepreferably 0.5 to 25 g/l and in particular 1 to 10 g/l.

[0046] The fixation of the compounds of formula (1) on the bulk materialsurface then may be initiated, for example, by irradiation, particularlyby irradiation with UV or visible light. Suitable light sources for theirradiation are known to the artisan and comprise for example mercurylamps, high pressure mercury lamps, xenon lamps, carbon arc lamps orsunlight. Sensitizers may be used to shift the irradiation wavelength.In addition, a suitable filter may be used to limit the irradiation to aspecific wavelength range. Preferably, the bulk material surface towhich the compound(s) of formula (1) have been previously applied, isirradiated with light of a wavelength≧250 nm and preferably≧300 nm. Thetime period of irradiation is not critical but is usually in the rangeof up to 30 minutes, preferably from 10 seconds to 10 minutes, and morepreferably from 15 seconds to 5 minutes, and particularly preferablyfrom 20 seconds to 1 minute. The irradiation may be carried out underambient conditions or in an atmosphere of inert gas. Masks can be usedfor the generation of specific surface patterns of functional groups.Following the fixation reaction, any non-covalently bound compounds canbe removed, for example by treatment, e.g. extraction, with suitablesolvents, for example water, C₁-C₄-alkanols, water/C₁-C₄-alkanolmixtures or acetonitrile.

[0047] Depending on the desired concentration of functional groups L₂ onthe material surface, the above outlined process cycle, (i) contacting,i.e. spraying or dipping, the surface with the compound(s) of formula(1) and (ii) fixing the compound(s) of formula (1) on the surface, i.e.by irradiation, may be carried out once or, preferably, several times.For example, 1 to 100, preferably 1 to 50 and in particular 5 to 25,different layers of one or more compounds of formula (1) are added andfixed on the material surface.

[0048] A polymerization initiator according to step (a) is typically onethat is initiating a radical polymerization of ethylenically unsaturatedcompounds. The radical polymerization may be induced thermally, orpreferably by irradiation.

[0049] Initiators for the thermal polymerization are particularlyfunctional initiators having an initiator part such as a peroxide,hydroperoxide, persulfate or azo group and in addition a functionalgroup that is co-reactive with the functional groups L₂ of the modifiedbulk material surface obtainable, for example, as described above or asdisclosed in WO 99/57581. Suitable functional groups that areco-reactive with L₂ are, for example, a carboxy, amino, hydroxy, epoxyor isocyanato group.

[0050] Initiators for the radiation-induced polymerization areparticularly functional photoinitiators having a photoinitiator part andin addition a functional group that is co-reactive with the functionalgroups introduced to the bulk material surface by a plasma treatmentaccording to step (i), or that is co-reactive with the functional groupsL₂ of the bulk material surface modified according step (ii). Thephotoinitiator part may belong to different types, for example to thethioxanthone type and preferably to the benzoin type. Suitablefunctional groups that are co-reactive with L₂ are, for example, acarboxy, amino, hydroxy, epoxy or isocyanato group.

[0051] Preferred polymerization initiators for use in the presentinvention are the photoinitiators of formulae (I) and (Ia) as disclosedin U.S. Pat. No. 5,527,925, those of the formula (I) as disclosed in PCTapplication WO 96/20919, or those of formulae II and III includingformulae IIa-IIy and IIIg as disclosed in EP-A-0281941, particularlyformulae IIb, IIi, IIm, IIn, IIp, IIr, IIs, IIx and IIIg therein.

[0052] The polymerization initiator moieties are preferably derived froma functional photoinitiator of the formula

[0053] wherein b1 and b2 are each 0, Z and Z₁ are each bivalent —O—, b3is 0 or 1; R₄ is methyl or phenyl, or both groups R₄ together arepentamethylene; R₅ is methyl or H; R₃ is hydrogen; a is 1 and R₂ isethylene, or a is 0 and R₂ is a direct bond; a1 is 0 or 1; and R₁ isbranched C₆-C₁₀-alkylene, phenylene or phenylene substituted by from 1to 3 methyl groups, benzylene or benzylene substituted by from 1 to 3methyl groups, cyclohexylene or cyclohexylene substituted by from 1 to 3methyl groups, cyclohexyl-CH₂— or cyclohexyl-CH₂— substituted by from 1to 3 methyl groups,

[0054] T is bivalent —O—; Z₂ is —O—(CH₂)_(y)— wherein y is an integerfrom 1 to 4 and the terminal CH₂ group of which is linked to theadjacent T in formula (3c); R₃ is H; R₈ is methyl, allyl, tolylmethyl orbenzyl, R₉ is methyl, ethyl, benzyl or phenyl, or R₈ and R₉ together arepentamethylene, R₁₀ and R₁₁ are each independently of the otherC₁-C₄-alkyl or R₁₀ and R₁₁ together are —CH₂CH₂OCH₂CH₂—, and R₆ isbranched C₆-C₁₀-alkylene, phenylene or phenylene substituted by from 1to 3 methyl groups, benzylene or benzylene substituted by from 1 to 3methyl groups, cyclohexylene or cyclohexylene substituted by from 1 to 3methyl groups, cyclohexylene-CH₂— or cyclohexylene-CH₂— substituted byfrom 1 to 3 methyl groups.

[0055] Photoinitiators of formula (3a) and (3b) are particularlypreferred.

[0056] Some examples of especially preferred functional photoinitiatorsare the compounds of formulae

[0057] or

OCN—CH₂—C(CH₃)₂—CH₂—CH(CH₃)—CH₂—CH₂—NH—C(O)—O—R₂₂  (3d₃)

[0058] wherein R₂₂ is a radical

[0059] The reactions of radicals on the material surface that arederived from a compound of formula (1) having a carboxy, carboxyderivative, isocyanato or isothiocyanato group L₂ with a functionalpolymerisation initiator having an amino or hydroxy group, or viceversa, are well-known in the art and may be carried out as desribed intextbooks of organic chemistry. For example, the reaction of a radicalderived from a compound of formula (1), wherein L₂ is an isocyanato orisothiocyanato group with an amino- or hydroxy-functionalizedpolymerisation initiator, or vice versa the reaction of an amino- orhydroxy group L₂ with an isocyanato or isothiocyanato functionalizedpolymerisation initiator, may be carried out in an inert organic solventsuch as an optionally halogenated hydrocarbon, for example petroleumether, methylcyclohexane, toluene, chloroform, methylene chloride andthe like, or an ether, for example diethyl ether, tetrahydrofurane,dioxane, or a more polar solvent such as DMSO, DMA, N-methylpyrrolidoneor even a lower alcohol, at a temperature of from 0 to 100° C.,preferably from 0 to 50° C. and particularly preferably at roomtemperature, optionally in the presence of a catalyst, for example atertiary amine such as triethylamine or tri-n-butylamine,1,4-diazabicyclooctane, or a tin compound such as dibutyltin dilaurateor tin dioctanoate. It is advantageous to carry out the above reactionsunder an inert atmosphere, for example under a nitrogen or argonatmosphere.

[0060] In case that the radicals on the material surface are derivedfrom a compound of formula (1) having a carboxy group L₂, the reactionof the carboxy group with an amino or hydroxy group functionalizedphotoinitiator, or vice versa the reaction of an amino or hydroxy groupL₂ with a carboxy functionalized polymerisation initiator, may becarried out under the conditions that are customary for ester or amideformation, for example in an aprotic medium at a temperature from aboutroom temperature to about 100° C. It is further preferred to carry outthe esterification or amidation reaction in the presence of anactivating agent, for exampleN-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxysuccinimide (NHS), sulfo-N-hydroxy succinimide or N,N′-dicyclohexylcarbodiimide (DCC) or in the presence of an o-(benztriazole)-uroniumsalt such as o-(benztriazol-1-y-)-N,N,N,N-tetramethyluroniumhexafluorophosphate. Most preferably, the carboxy group L₂ is previouslyconverted to an activated ester using one of the above-mentionedactivating agents, and the activated ester is then further reacted withthe hydroxy or preferably amino groups of the surface.

[0061] In a preferred embodiment of the invention, L₂ comprises amino,alkylamino or hydroxy, particularly amino, as reactive group and theco-reactive group of the polymerization initiator is an isocyanatogroup. A preferred polymerization initiator of this embodiment is aphotoinitiator of the above formula (3b), (3c), (3d₁), (3d₂) or (3d₃).

[0062] According to another preferred embodiment of the invention, L₂comprises carboxy, a carboxy derivative, isocyanato or isothiocyanato asreactive group, and the co-reactive group of the polymerizationinitiator is a hydroxy, amino, alkylamino or thiol group, particularlyan amino group. A preferred polymerization initiator of this embodimentis a photoinitiator of the above formula (3a).

[0063] Hydrophilic ethylenically unsaturated macromonomers for graftpolymerization from the bulk material surface according to step (b) ofthe process of the present invention are known, for example, from WO99/57581. A suitable macromonomer is, for example of formula

[0064] wherein R₃₂ is hydrogen, C₁-C₆-alkyl or a radical —COOR′;

[0065] R, R′ and R₃₂′ are each independently of the other hydrogen orC₁-C₆-alkyl;

[0066] A is a direct bond or is a radical of formula

—C(O)—(A₁)_(n)—X—  (5a)

[0067] or

—(A₂)_(m)—NH—C(O)—X—  (5b)

[0068] or

—(A₂)_(m)—X—C(O)—  (5c)

[0069] or

—C(O)—NH—C(O)—X—  (5d)

[0070] or

—C(O)—X₁—(alk*)—X—C(O)—  (5e)

[0071] or

[0072] A and R₃₂, together with the adjacent double bond, are a radicalof formula

[0073] A₁ is —O—C₂-C₁₂-alkylene which is unsubstituted or substituted byhydroxy, or is —O—C₂-C₁₂-alkylene-NH—C(O)— or—O—C₂-C₁₂-alkylene-O—C(O)—NH—R₃₃—NH—C(O)— or —NH—(Alk*)—C(O)—, wherein(Alk*) is C₁-C₆-alkylene and R₃₃ is linear or branched C₁-C₁₈-alkyleneor unsubstituted or C₁-C₄-alkyl- or C₁-C₄-alkoxy-substitutedC₆-C₁₀-arylene, C₇-C₁₈-aralkylene,C₆-C₁₀-arylene-C₁-C₂-alkylene-C₆-C₁₀-arylene, C₃-C₈-cycloalkylene,C₃-C₈-cycloalkylene-C₁-C₆-alkylene, C₃-C₈-cycloalkylene-C₁-C₂-alkylene-C₃-C₈-cycloalkylene or C₁-C₆-alkylene-C₃-C₈-cycloalkylene-C₁-C₆-alkylene

[0074] A₂ is C₁-C₈-alkylene; phenylene or benzylene;

[0075] m and n are each independently of the other the number 0 or 1;

[0076] X, X₁ and X′ are each independently of the other a bivalent group—O— or —NR″, wherein R″ is hydrogen or C₁-C₆-alkyl;

[0077] (alk*) is C₂-C₁₂-alkylene;

[0078] and (oligomer) denotes

[0079] (i) the radical of a telomer of formula

[0080] wherein (alk) is C₂-C₁₂-alkylene,

[0081] Q is a monovalent group that is suitable to act as apolymerization chain-reaction terminator,

[0082] p and q are each independently of another an integer from 0 to350, wherein the total of (p+q) is an integer from 2 to 350,

[0083] and B and B′ are each independently of the other a 1,2-ethyleneradical derivable from a copolymerizable vinyl monomer by replacing thevinylic double bond by a single bond, at least one of the radicals B andB′ being substituted by a hydrophilic substituent; or

[0084] (ii) the radical of an oligomer of the formula

[0085] wherein R₁₉ is hydrogen or unsubstituted or hydroxy-substitutedC₁-C₁₂-alkyl, u is an integer from 2 to 250 and Q′ is a radical of apolymerization initiator; or

[0086] (iii) the radical of formula

[0087] wherein R₁₉, X and u are as defined above, or

[0088] (iv) the radical of an oligomer of formula

[0089] wherein R₂₀ and R₂₀′ are each independently C₁-C₄-alkyl, An⁻ isan anion, v is an integer from 2 to 250, and Q″ is a monovalent groupthat is suitable to act as a polymerization chain-reaction terminator;or

[0090] (v) the radical of an oligopeptide of formula

—(CHR₂₁—C(O)—NH)_(t)—CHR₂₁—COOH  (6d)

[0091] or

—CHR₂₁—(NH—C(O)—CHR₂₁)_(t)—NH₂  (6d′)

[0092] wherein R₂₁ is hydrogen or C₁-C₄-alkyl which is unsubstituted orsubstituted by hydroxy, carboxy, carbamoyl, amino, phenyl, o- , m- orp-hydroxyphenyl, imidazolyl, indolyl or a radical —NH—C(═NH)—NH₂ and tis an integer from 2 to 250, or the radical of an oligopeptide based onproline or hydroxyproline; or

[0093] (vi) the radical of a polyalkylene oxide of formula

—(alk^(**)—O)_(z)—[CH₂—CH₂—O]_(r)—[CH₂—CH(CH₃)—O]_(s)—R₃₄  (6e)

[0094] wherein R₃₄ is hydrogen or C₁-C₂₄-alkyl, (alk^(**)) isC₂-C₄-alkylene, z is 0 or 1, r and s are each independently an integerfrom 0 to 250 and the total of (r+s) is from 2 to 250; or

[0095] (vii) the radical of an oligosaccharide;

[0096] subject to the provisos that

[0097] A is not a direct bond if (oligomer) is a radical of formula(6a);

[0098] A is a radical of formula (5a), (5b) or (5d) or A and R₃₂,together with the adjacent double bond, are a radical of formula (5f) if(oligomer) is a radical of formula (6b), (6c), (6d) or (6e) or is theradical of an oligosaccharide;

[0099] A is a direct bond if (oligomer) is a radical of formula (6b′);and

[0100] A is a radical of formula (5c) or (5e) if (oligomer) is a radicalof formula (6d′).

[0101] The following preferences apply to the variables contained in thedefinition of the macromonomer of formula (4):

[0102] R′ is preferably hydrogen or C₁-C₄-alkyl, more preferablyhydrogen or C₁-C₂-alkyl and particularly preferably hydrogen.

[0103] R₃₂ is preferably hydrogen, methyl or carboxyl, and particularlypreferably hydrogen.

[0104] R is preferably hydrogen or methyl.

[0105] X is preferably a bivalent group —O— or —NH—. X is particularlypreferably the group —NH— if (oligomer) is a radical of formula (6a);(6c) or (6d), and is particularly preferably the group —O— if (oligomer)is a radical of formula (6b) or (6e) or is the radical of anoligosaccharide. X′ is preferably —O— or —NH— and more preferably —NH—.X₁ is preferably —O— or —NH—.

[0106] The radical R₃₃ has a symmetrical or, preferably, an asymmetricalstructure. R₃₃ is preferably linear or branched C₆-C₁₀alkylene;cyclohexylene-methylene or cyclohexylene-methylene cyclohexylene eachunsubstituted or substituted in the cyclohexyl moiety by from 1 to 3methyl groups; or phenylene or phenylene-methylene-phenylene eachunsubstituted or substituted in the phenyl moiety by methyl. Thebivalent radical R₃₃ is derived preferably from a diisocyanate and mostpreferably from a diisocyanate selected from the group isophoronediisocyanate (IPDI), toluylene-2,4-diisocyanate (TDI),4,4′-methylenebis(cyclohexyl iso-cyanate),1,6-diisocyanato-2,2,4-trimethyl-n-hexane (TMDI), methylenebis(phenylisocyanate), methylenebis(cyclohexyl-4-isocyanate) and hexamethylenediisocyanate (HMDI).

[0107] Preferred meanings of A₁ are unsubstituted or hydroxy-substituted—O—C₂-C₈-alkylene or a radical —O—C₂-C₆-alkylene—NH—C(O)— andparticularly —O—(CH₂)₂₋₄—, —O—CH₂—CH(OH)—CH₂— or a radical—O—(CH₂)₂₋₄—NH—C(O)—. A particularly preferred meaning of A₁ is theradical —O—(CH₂)₂—NH—C(O)—.

[0108] A₂ is preferably C₁-C₆-alkylene, phenylene or benzylene, morepreferably C₁-C₄-alkylene and even more preferably C₁-C₂-alkylene.

[0109] n is an integer of 0 or preferably 1. m is preferably an integerof 1.

[0110] R₃₂′ is preferably hydrogen or methyl and particularly preferablyhydrogen.

[0111] In case that (oligomer) is a radical of formula (6a), (6b), (6c),(6d) or (6e) or is the radical of an oligosaccharide, is A preferably aradical of formula (5a) or (5b) and particularly preferably a radical offormula (5a), wherein the above given meanings and preferences apply forthe variables contained therein.

[0112] A preferred group of hydrophilic macromonomers according to theinvention comprises compounds of the above formula (4), wherein R ishydrogen or methyl, R₃₂ is hydrogen, methyl or carboxyl, R₃₂′ ishydrogen, A is a radical of the formula (5a) or (5b) and (oligomer) is aradical of formula (6a), (6b), (6c), (6d) or (6e) or is the radical ofan oligosaccharide. An even more preferred group of hydrophilicmacromonomers comprises compounds of the above formula (4), wherein R ishydrogen or methyl, R₃₂ and R₃₂′ are each hydrogen, A is a radical ofthe formula (5a) and (oligomer) is a radical of formula (6a). A furthergroup of preferred macromonomers comprises compounds of formula (4),wherein A is a radical of formula (5e) above and (oligomer) is a radicalof formula (6a).

[0113] (Alk*) is preferably methylene, ethylene or1,1-dimethyl-methylene, in particular a radical —CH₂— or —C(CH₃)₂—.(alk) and (alk*) are each independently preferably C₂-C₈-alkylene, morepreferably C₂-C₆-alkylene, even more preferably C₂-C₄-alkylene andparticularly preferably 1,2-ethylene. The alkylene radicals (alk) and(alk*) may be branched or preferably linear alkylene radicals.

[0114] Q is for example hydrogen.

[0115] The total of (p+q) is preferably an integer from 2 to 150, morepreferably from 5 to 100, even more preferably from 5 to 75 andparticularly preferably from 10 to 50. In a preferred embodiment of theinvention q is 0 and p is an integer from 2 to 250, preferably from 2 to150, more preferably from 5 to 100, even more preferably from 5 to 75and particularly preferably from 10 to 50.

[0116] Suitable hydrophilic substituents of the radicals B or B′ arethose described in WO 99/57581 on pages 16 to 24.

[0117] A group of preferred non-ionic substituents of B or B′ comprisesC₁-C₂-alkyl, which is unsubstituted or substituted by —OH or —NR₂₃R₂₃′,wherein R₂₃ and R₂₃′ are each independently of the other hydrogen orC₁-C₂-alkyl; a radical —COOY wherein Y is C₁-C₄-alkyl; C₂-C₄-alkyl whichis substituted by —OH, —NR₂₃R₂₃′ wherein R₂₃ and R₂₃′ are eachindependently of another hydrogen or C₁-C₂-alkyl, or Y is a radical—C₂-C₄-alkylene—NH—C(O)—O—G wherein —O—G is the radical of a saccharide;a radical —C(O)—NY₁Y₂, wherein Y₁ and Y₂ are each independently of theother hydrogen or C₁-C₆-alkyl which is unsubstituted or substituted byhydroxy, or Y₁ and Y₂ together with the adjacent N-atom form aheterocyclic 6-membered ring having no further heteroatom or having onefurther N- or O-atom; a radical —OY₃, wherein Y₃ is hydrogen,C₁-C₄-alkyl which is unsubstituted or substituted by —NH₂ or—N(C₁-C₂-alkyl)₂, or is a group —C(O)C₁-C₂-alkyl; or a 5- or 6-memberedheteroaromatic or heteroaliphatic radical having one N-atom and inaddition no further heteroatom or an additional N- , O- or S-heteroatom,or a 5 to 7-membered lactame.

[0118] A group of more preferred non-ionic substituents of B or B′comprises a radical —COOY, wherein Y is C₁-C₂-alkyl, C₂-C₃-alkyl, whichis substituted by hydroxy, amino or N,N-di-C₁-C₂-alkylamino, or is aradical -C₂-C₄-alkylene—NH—C(O)—O—G wherein —O—G is the radical oftrehalose; a radical —CO—NY₁Y₂, wherein Y₁ and Y₂ are each independentlyof the other hydrogen or C₁-C₄-alkyl which is unsubstituted orsubstituted by hydroxy, or Y₁ and Y₂ together with the adjacent N-atomform a N—C₁-C₂-alkylpiperazino or morpholino ring; or a heterocyclicradical selected from the group consisting of N-pyrrolidonyl, 2- or4-pyridinyl, 2-methylpyridin-5-yl, 2-, 3- oder 4-hydroxypyridinyl,N-ε-caprolactamyl, N-imidazolyl, 2-methylimidazol-1-yl, N-morpholinyland 4-N-methylpiperazin-1-yl.

[0119] A particularly preferred group of non-ionic substituents of B orB′ comprises the radicals —CONH₂, —CON(CH₃)₂,

[0120] —CONH—(CH₂)₂—OH, —COO—(CH₂)₂—N(CH₃)₂, and —COO(CH₂)₂₋₄—NHC(O)—O—Gwherein —O—G is the radical of trehalose.

[0121] Particularly preferred anionic substituents of B or B′ are —COOH,—SO₃H, o-, m- or p-sulfophenyl, o-, m- or p-sulfomethylphenyl or aradical —CONY₅Y₆ wherein Y₅ is C₂-C₄-alkyl substituted by sulfo, and Y₆is hydrogen.

[0122] A preferred cationic substituent of B or B′ is a radical —C(O)OY₇wherein Y₇ is C₂-C₄-alkyl, which is substituted by —N(C₁-C₂-alkyl)₃ ⁺An⁻and is further substituted by hydroxy, and An⁻ is an anion, for examplethe radical —C(O)O—CH₂—CH(OH)—CH₂—N(CH₃)₃ ⁺An⁻.

[0123] A preferred group of zwitter-ionic substituents —R₂₄—Zwcorresponds to the formula

—C(O)O—(alk′″)—N(R₂₃)₂ ⁺—(alk′)—An⁻

[0124] or

—C(O)O—(alk″)—O—PO₂—(O)₀₋₁—(alk′″)—N(R₂₃)₃ ⁺

[0125] wherein R₂₃ is hydrogen or C₁-C₆-alkyl; An⁺ is an anionic group—COO⁻, —SO₃ ⁻, —OSO₃ ⁻ or —OPO₃H⁻, preferably —COO⁻ or —SO₃ ⁻ and mostpreferably —SO₃ ⁻, alk′ is C₁-C₁₂-alkylene, (alk″) is C₂-C₂₄-alkylenewhich is unsubstituted or substituted by a radical —OY₈, Y₈ is hydrogenor the acyl radical of a carboxylic acid, and (alk′″) is C₂-C₈-alkylene.

[0126] (alk′) is preferably C₂-C₈-alkylene, more preferablyC₂-C₆-alkylene and most preferably C₂-C₄-alkylene. (alk″) is preferablyC₂-C₁₂-alkylene, more preferably C₂-C₆-alkylene and particularlypreferably C₂-C₃-alkylene which is in each case unsubstituted orsubstituted by hydroxy or by a radical —OY₈. (alk′″) is preferablyC₂-C₄-alkylene and more preferably C₂-C₃-alkylene. R₂₃ is hydrogen orC₁-C₄-alkyl, more preferably methyl or ethyl and particularly preferablymethyl. A preferred zwitterionic substituent of B or B′ is of formula

—C(O)O—CH₂—CH(OY₈)—CH₂—O—PO₂ ⁻—(CH₂)₂—N(CH₃)₃ ⁺

[0127] wherein Y₈ is hydrogen or the acyl radical of a higher fattyacid.

[0128] B denotes for example a radical of formula

[0129] wherein R₂₅ is hydrogen or C₁-C₄-alkyl, preferably hydrogen ormethyl; R₂₆ is a hydrophilic substituent, wherein the above givenmeanings and preferences apply; R₂₇ is C₁-C₄-alkyl, phenyl or a radical—C(O)OY₉, wherein Y₉ is hydrogen or unsubstituted or hydroxy-substitutedC₁-C₄-alkyl; and R₂₈ is a radical —C(O)Y₉′ or —CH₂—C(O)OY₉′ wherein Y₉′independently has the meaning of Y₉.

[0130] R₂₇ is preferably C₁-C₂-alkyl, phenyl or a group —C(O)OY₉. R₂₈ ispreferably a group —C(O)OY₉′ or —CH₂—C(O)OY₉′ wherein Y₉ and Y₉′ areeach independently of the other hydrogen, C₁-C₂-alkyl orhydroxy-C₁-C₂-alkyl. Particularly preferred —CHR₂₇—CHR₂₈— unitsaccording to the invention are those wherein R₂₇ is methyl or a group—C(O)OY₉ and R₂₈ is a group —C(O)OY₉′ or —CH₂—C(O)OY₉′ wherein Y₉ andY₉′ are each hydrogen, C₁-C₂-alkyl or hydroxy-C₁-C₂-alkyl.

[0131] B′ independently may have one of the meanings given above for B.

[0132] If (oligomer) is a radical of formula (6a), the radical—(alk)—S—[B]_(p)—[B′]_(q)—Q preferably denotes a radical of formula

[0133] even more preferably of the formula

[0134] wherein for R₂₅, R₂₆, Q, p and q the above-given meanings andpreferences apply, for R₂₅′ independently the meanings and preferencesgiven before for R₂₅ apply, and for R₂₆′ independently the meanings andpreferences given before for R₂₆ apply.

[0135] A preferred group of suitable hydrophilic macromonomers accordingto step (b) of the invention comprises compounds of formula

[0136] wherein R is hydrogen or methyl, A₁ is —O—(CH₂)₂₄—,—O—CH₂—CH(OH)—CH₂— or a radical —O—(CH₂)₂₋₄—NH—C(O)—, X is —O— or —NH—,(alk) is C₂-C₄-alkylene, Q is a monovalent group that is suitable to actas a polymerization chain-reaction terminator, p is an integer from 5 to50, R₂₅ and R₂₅′ are each independently of the other hydrogen or methyl,and for R₂₆ and R₂₆′ each independently the above given meanings andpreferences apply.

[0137] A particularly preferred embodiment of the invention relates tohydrophilic macromonomers of the formula

[0138] wherein for R, R₂₅, R₂₆, Q, (alk) and p the above-given meaningsand preferences apply. A particularly preferred group of hydrophilicmacromonomers are compounds of the above formula (4b) wherein R ishydrogen or methyl, (alk) is C₂-C₄-alkylene, R₂₅ is hydrogen or methyl,p is an integer of 5 to 50, Q is as defined before, and for R₂₆ theabove given meanings and preferences apply; in particular R₂₆ of thisembodiment is a radical —CONH₂, —CON(CH₃)₂ or

[0139] If (oligomer) is a radical (ii) of formula (6b), Q′ in formula(6b) is for example C₁-C₁₂-alkyl, phenyl or benzyl, preferablyC₁-C₂-alkyl or benzyl and in particular methyl. R₁₉ is preferablyunsubstituted or hydroxy-substituted C₁-C₄-alkyl and in particularmethyl. u is preferably an integer from 2 to 150, more preferably from 5to 100, even more preferably from 5 to 75 and particularly preferablyfrom 10 to 50.

[0140] If (oligomer) is a radical of formula (6b′), the above givenmeanings and preferences apply for the variables R₁₉ and u containedtherein. X in formula (6b′) is preferably hydroxy or amino.

[0141] If (oligomer) denotes a radical (iv) of formula (6c), R₂₀ andR₂₀′ are each preferably ethyl or in particular methyl; v is preferablyan integer from 2 to 150, more preferably from 5 to 100, even morepreferably from 5 to 75 and particularly preferably from 10 to 50; Q″ isfor example hydrogen; and An⁻ is as defined before.

[0142] If (oligomer) denotes an oligopeptide radical (v) of formula (6d)or 6d′), R₂₁ is for example hydrogen, methyl, hydroxymethyl,carboxymethyl, 1-hydroxyethyl, 2-carboxyethyl, isopropyl, n-, sec. oriso-butyl, 4-amino-n-butyl, benzyl, p-hydroxybenzyl, imidazolylmethyl,indolylmethyl or a radical —(CH₂)₃—NH—C(═NH)—NH₂. t is preferably aninteger from 2 to 150, more preferably from 5 to 100, even morepreferably from 5 to 75 and particularly preferably from 10 to 50.

[0143] If (oligomer) denotes a polyoxyalkylene radical (vi) of formula(6e), R₃₄ is preferably hydrogen or C₁-C₁₈-alkyl, more preferablyhydrogen or C₁-C₁₂-alkyl, even more preferably hydrogen, methyl orethyl, and particularly preferably hydrogen or methyl. (alk **) ispreferably a C₂-C₃-alkylene radical. z is preferably 0. r and s are eachindependently preferably an integer from 0 to 100 wherein the total of(r+s) is 5 to 100. r and s are each independently more preferably aninteger from 0 to 50 wherein the total of (r+s) is 8 to 50. In aparticularly preferred embodiment of the polyoxyalkylene radicals(oligomer), r is an integer from 8 to 50 and particularly 9 to 25, and sis 0. (oligomer) as the radical of an oligosaccharide (vii) may be, forexample, a di- or polysaccharide including carbohydrate containingfragments from a biopolymer. Examples are the radical of a cyclodextrin,trehalose, cellobiose, maltotriose, maltohexaose, chitohexaose or astarch, hyaluronic acid, deacetylated hyaluronic acid, chitosan,agarose, chitin 50, amylose, glucan, heparin, xylan, pectin, galactan,glycosaminoglycan, mucin, dextran, aminated dextran, cellulose,hydroxyalkylcellulose or carboxyalkylcellulose oligomer, each of whichwith a molecular weight average weight of, for example, up to 25,000 Da,preferably up to 10,000 Da. Preferably the oligosaccharide according to(vii) is the radical of a cyclodextrin with a maximum of 8 sugar units.

[0144] Formulae (6a), (6a′) or (6e) are to be understood as a statisticdescription of the respective oligomeric radicals, that is to say, theorientation of the monomers and the sequence of the monomers (in case ofcopolymers) are not fixed in any way by said formulae. The arrangementof B and B′ in formula (6a) or of the ethyleneoxide and propyleneoxideunits in formula (6e) thus in each case may be random or blockwise.

[0145] The weight average molecular weight of the hydrophilicmacromonomer according to step (b) depends principally on the desiredproperties and is for example from 300 to 25000 Da, preferably from 300to 12,000 Da, more preferably from 300 to 8000 Da, even more preferablyfrom 300 to 5000 Da, and particularly preferably from 500 to 4000 Da.

[0146] The macromonomers of formula (4) may be prepared by methods knownper se, as described in, for example, WO 99/57581.

[0147] A wide variety of structurally different polymers are suitablefor use in step (b) of the present invention subject to the conditionthat said polymers lack polymerizable ethylenically unsaturated groupsand are hydrophilic and biocompatible. Suitable biocompatiblehydrophilic polymers comprise, for example, biopolymers, modifiedbiopolymers and synthetic polymers.

[0148] The weight average molecular weight M_(w) of biocompatiblehydrophilic polymers according to step (b) depends principally on thedesired properties and is from 1000 to 5,000,000 Da, preferably from10,000 to 1,000,000 Da, and particularly preferably from 100,000 to500,000 Da.

[0149] Examples of suitable biopolymers are polysaccharides, forexample, hyaluronic acid, chondriotin sulfate, dextran, 1,3-glucan,fucoidan; glycoproteins, for example, mucin, fibronectin; glucosamines,for example chitin, chitosan, heparin; polypeptides, for example,lysozyme, collagen; proteins, for example albumen, immunoglobulines.

[0150] Examples of suitable modified biopolymers are, for example,carboxyalkylcellulose, for example carboxymethylcellulose,carboxyalkylchitin, carboxyalkylchitosan.

[0151] Examples of suitable synthetic polymers arebis-aminoalkylene-polyalkylene glycols of various average molecularweights, for example a Jeffamine® polyoxyalkylene amines;polyethyleneglycols, poly(hydroxyethyl methacrylate (poly-HEMA), highmolecular weight, crosslinked, acrylic acid based polymers, for example,Carbopol® polymers and Noveon® Polycarbophils; polyacrylamide,polyvinylpyrrolidone, polyvinyl alcohol.

[0152] Preferred biocompatible hydrophilic polymers are highly branchedand/or possess molecular weights>40,000 Da. Especially preferred arehyarulonic acid, dextran, heparin, chondriotin sulfate, mucin,polyvinylpyrrolidone or a Polycarbophil or Carbopol® polymer.

[0153] The biocompatible hydrophilic polymer is not covalently bonded tothe polymer chains of the macromonomer. Chain entanglement, hydrogenbonds, Van der Waals forces and charge interactions are among the mostimportant interactions between the hydrophilic macromonomers graftedfrom the bulk material and the biocompatible hydrophilic polymer. Theseforces stabilize the entangled biocompatible hydrophilic polymer andprevent it's rapid leaching from the interpenetration mixture underphysiological conditions. Preferably, the biocompatible hydrophilicpolymers contribute significantly to specific advantageous features ofthe s-IPN-structured coating. Among those are for example: lubrication,water retention and stabilization of aqueous surface layers,biocompatibility, reversible attraction of biomolecules (e.g. mucins)from biological fluids, prevention of irreversible deposition ofproteins, lipids and salts and inhibition of microbial adhesion.Controlled low rate leaching of entangled biocompatible hydrophilicpolymers out of the contact lens coatings can enhance lubricity andcomfort, and in addition can favour a continuous renewal of the lenssurface.

[0154] Additional components can be included within the s-IPN. They caneither be uncrosslinked polymers, oligomers or low molecular weightcomponents with their leaching rates from the s-IPN naturally increasingwith descreasing molecular masses. An additional component is preferablya bioactive material or a bioactive polymer. In a particular embodimentof the invention an additional component can be an enzyme, an antibody,an antimicrobial peptide, a polyquat or a growth factor. It ischaracteristic for additional components that they slowly release fromthe coating under physiological conditions.

[0155] The practical use of devices and articles carrying coatingsaccording to the disclosed technology can be seen in technical, inbiological and in environmental systems. Applications in the biomedicalfield are preferred: in particular, coatings for ophthalmic devices andimplants, such as contact lenses, ocular drug delivery systems,intraocular lenses and artificial corneas.

[0156] In addition, s-IPN coatings of the present invention areoutstanding with regard to their capability of lubricating contact lenssurfaces and thus reducing the blinking frequency and the overallwearing comfort of contact lens users. By lubricating the cornea surface(via leachables) contact lens coatings of the present invention canimprove the on-eye mobility of contact lens. All this is of particularimportance with regard to extended wear contact lenses. Theseadvantageous effects can be caused or be enhanced by leaching of Band/or C. The surface coatings of the invention can also be applied toophthalmic implants. In technical applications coatings of the presentinvention can prevent befouling of separation membranes and can reducefriction, calcification, scale and drag phenomena in hydrodynamicsystems.

[0157] The mixture of hydrophilic macromonomers and biocompatiblehydrophilic polymer may be applied to the initiator-modified materialaccording to processes known per se. For example, the materialcomprising the covalently bound polymerisation initiator is immersed ina solution of the macromonomer and biocompatible hydrophilic polymer, ora layer of said solution is first of all deposited on the modifiedmaterial surface, for example, by dipping, spraying, spreading, knifecoating, pouring, rolling, spin coating or vacuum vapor deposition.Suitable solvents, if used in the polymerization process, are, forexample, water or dipolar aprotic solvents such as, for example,acetonitrile. The polymerization of the hydrophilic macromonomer on thematerial surface then may be initiated , for example, thermally by theaction of heat or preferably by irradiation, particularly by UVradiation. Suitable light sources for the irradiation are known to theartisan and comprise for example mercury lamps, high-pressure mercurylamps, xenon lamps, carbon arc lamps or sunlight. The time period ofirradiation may depend for example on the desired properties of theresulting composite material but is usually in the range of up to 30minutes, preferably from 10 seconds to 10 minutes, and particularlypreferably from 0.5 to 5 minutes. It is advantageous to carry out theirradiation in an atmosphere of inert gas.

[0158] The coated material obtained according to the invention may bepurified afterwards in a manner known per se, for example by washing orextraction with a suitable solvent such as water.

[0159] By means of process step (b) of the above-described coatingprocess, the hydrophilic macromonomers may be grafted to the materialsurface with formation of a coating having, for example, a so-calledbottle brush-type structure (BBT) composed of tethered “hairy” chains.Such BBT structures in one embodiment comprise a long hydrophilic orhydrophobic backbone, which carries relatively densely, packedcomparatively short hydrophilic side chains (called primary bottlebrushes). Another embodiment relates to secondary bottle brushes whichare characterized in that the hydrophilic side chains themselves carrydensely packed hydrophilic “secondary” side chains. Polymeric coatingsof said primary and secondary BBT structures to a certain extent mimichighly water-retaining structures occurring in the human body, forexample in cartilage or mucosal tissue.

[0160] A further embodiment of the invention relates to a material thatis coated by the process of the invention.

[0161] The material that is coated by the process of the invention is,for example, an organic bulk material, preferably a biomedical device,e.g. an ophthalmic device, preferably a contact lens including both hardand particularly soft contact lenses, an intraocular lens or artificialcornea. Further examples are materials useful for example as woundhealing dressings, eye bandages, materials for the sustained release ofan active compound such as a drug delivery patch, moldings that can beused in surgery, such as heart valves, vascular grafts, catheters,artificial organs, encapsulated biologic implants, e.g. pancreaticislets, materials for prostheses such as bone substitutes, or moldingsfor diagnostics, membranes or biomedical instruments or apparatus.

[0162] The biomedical devices, e.g. ophthalmic devices obtainedaccording to the invention have a variety of unexpected advantages overthose of the prior art which make those devices very suitable forpractical purposes, e.g. as contact lens for extended wear orintraocular lens. For example, they do have a high surface wettability,which can be demonstrated by their contact angles, their water retentionand their water-film break up time or tear film break up time (TBUT).

[0163] The TBUT plays a particularly important role in the field ofophthalmic devices such as contact lenses. Thus the facile movement ofan eyelid over a contact lens has proven important for the comfort ofthe wearer; this sliding motion is facilitated by the presence of acontinuous layer of tear fluid on the contact lens, a layer thatlubricates the tissue/lens interface. However, clinical tests have shownthat currently available contact lenses partially dry out betweenblinks, thus increasing friction between eyelid and the lens. Theincreased friction results in soreness of the eyes and reduced movementof the contact lenses. Now it has become feasible to considerablyincrease the TBUT of commercial contact lenses such as, for example,those made of nelfilcon A, vifilcon A or lotrafilcon A polymer, byapplying a surface coating according to the invention. On the base curveof a contact lens, the pronounced lubricity of the coating facilitatesthe on-eye lens movement, which is essential for extended wear ofcontact lenses. Moreover, the materials obtained by the process of theinvention provide additional effects being essential for lenses forextended wear, such as an increased thickness of the pre-lens tear filmwhich contributes substantially to low microbial adhesion and resistanceto deposit formation. Due to the very slow release of the biocompatiblehydrophilic polymer the surface coatings according the present inventionare extremely soft and lubricious. Biomedical articles such as inparticular contact lenses coated by the process of the invention show asuperior wearing comfort including improvements with respect to late daydryness and long term (overnight) wear. The novel surface coatingsmoreover interact in a reversible manner with ocular mucus, whichcontributes to the improved wearing comfort.

[0164] In addition, biomedical devices, e.g. ophthalmic devices such ascontact lenses, coated by the process of the invention, have a verypronounced biocompatibility combined with good mechanical properties.For example, the devices are blood compatible and have good tissueintegration. In addition, there are generally no adverse eye effectsobserved, while the adsorption of proteins or lipids are low, also thesalt deposit formation is lower than with conventional contact lenses.Generally, there is low fouling, low microbial adhesion and low bioerosion while good mechanical properties can be for example found in alow friction coefficient and low abrasion properties. Moreover, thedimensional stability of the materials obtained according to theinvention is excellent. In addition, the attachment of a hydrophilicsurface coating at a given bulk material according to the invention doesnot affect its visual transparency.

[0165] In summary, the ophthalmic devices obtained by the process of theinvention, such as contact lenses and artificial cornea, provide acombination of low spoilation with respect to cell debris, cosmetics,dust or dirt, solvent vapors or chemicals, with a high comfort for thepatient wearing such ophthalmic devices in view of the soft hydrogelsurface which for example provides a very good on-eye movement of theophthalmic device.

[0166] Biomedical devices such as renal dialysis membranes, bloodstorage bags, pacemaker leads or vascular grafts coated by the processof the invention resist fouling by proteins by virtue of the continuouslayer of bound water, thus reducing the rate and extent of thrombosis.Blood-contacting devices fabricated according to the present inventionare therefore haemocompatible and biocompatible.

[0167] In the examples, if not indicated otherwise, amounts are amountsby weight, temperatures are given in degrees Celsius. Tear break-up timevalues in general relate to the pre-lens tear film non-invasive break-uptime (PLTF-NIBUT) that is determined following the procedure publishedby M. Guillon et al., Ophthal. Physiol. Opt. 9, 355-359 (1989) or M.Guillon et al., Optometry and Vision Science 74, 273-279 (1997). Averageadvancing and receding water contact angles of coated and non-coatedlenses are determined with the dynamic Wilhelmy method using a KrüssK-12 instrument (Krüss GmbH, Hamburg, Germany). Wetting force on thesolid is measured as the solid is immersed in or withdrawn from a liquidof known surface tension.

EXAMPLE A-1 1,2-Diaminocyclohexane Plasma Coating (DACH)

[0168] Two dried Lotrafilcon A lenses (polysiloxane/perfluoroethercopolymer) are, after extraction in isopropanol, toluene and again inisopropanol, placed on the glass holder within the plasma reactorequipped with an external ring electrode and a 27.13 MHz radiofrequency(RF) generator for the generation of an inductively-coupled, cold glowdischarge plasma. The distance between the substrates and the lower edgeof the plasma zone is 12 cm. The reactor is evacuated to a pressure of0.008 mbar, and held at these conditions for 1 h. Then, the argon plasmagas flow rate into the plasma zone of the reactor is set to 20 sccm(standard cubic centimeter), the pressure in the reactor is adjusted to0.12 mbar and the RF generator is switched on. The plasma discharge of apower 250 Watts is maintained for a total period of 1 min (in order toclean and activate the lenses surfaces). Afterwards the 1,2-DACH vaporis introduced into the reactor chamber from DACH reservoir (maintainedat 24° C.) at 0.15 mbar for 1 min. After this, the following parametersfor the plasma polymerization of DACH are chosen: Argon flow rate forplasma excitation=5 sccm, Argon carrier gas flow rate for DACHtransport=5 sccm, temperature of the DACH evaporation unit=24° C., thedistance between the lower edge of the plasma zone and the substrates=5cm, pressure=0.2 mbar, and plasma power=100 W. The lenses are treatedfor about 5 min with a pulsing glow discharge plasma (1 μsec. on, 3μsec. off). After 5 min of deposition the plasma discharge isinterrupted and DACH vapor is let to flow into reactor for additional 5min. The reactor is then evacuated and maintained for 30 min at apressure 0.008 mbar in order to remove residual monomer and activatedspices. The internal pressure is brought to atmospheric by using drynitrogen. The substrates are then turned over and the whole procedure isrepeated to coat the other side of the substrates. The samples are thenunloaded from the reactor and used for the subsequent photoinitiatorlinkage.

EXAMPLE A-2 Plasma Induced 2-Isocyanatoethyl Methacrylate Coating(Poly-IEM)

[0169] Lotrafilcon A contact lenses are, after extraction inisopropanol, placed on the Teflon holder within the plasma reactorequipped with external ring electrodes. The distance between thesubstrates and the lower edge of the plasma electrodes is 12 cm. Thereactor is evacuated to a pressure of 0.010 mbar, and held at theseconditions for 1 h. Then, the argon plasma gas flow rate into the plasmazone of the reactor is set to 20 sccm, the pressure in the reactor isadjusted to 0.07 mbar and the RF generator (27.12 MHz radio frequencygenerator, HFA Koppold & Co., Höhenkirchen, Germany) is switched on. Theplasma discharge of a power 170 Watts is maintained for a total periodof 1 min. Afterwards, the IEM vapor is introduced into the reactorchamber from IEM reservoir (maintained at 25° C.) at 0.15 mbar for 1min. After this, the following parameters for the plasma inducedpolymerization of IEM are chosen: Argon flow rate for plasmaexcitation=20 sccm, argon carrier gas flow rate for monomer (IEM)transport=10 sccm, temperature of the monomer (IEM) evaporation unit=25°C., the distance between the lower edge of the plasma electrodes and thesubstrates=16 cm, pressure=0.10 mbar, and plasma power=60 W. After 5 minof deposition, the plasma discharge is interrupted; the reactor isevacuated and maintained for 30 min at a pressure 0.010 mbar. Theinternal pressure is then brought to atmospheric pressure by using drynitrogen. The substrates are then turned over and the whole procedure isrepeated to coat the other side of the substrates. The samples are thenunloaded from the reactor and analyzed by ATR-FTIR measurements. Strongbands at about 2270 cm-1, which are characteristic for N═C═O groups, areclearly identified on all modified surfaces.

EXAMPLES A-3-A-6 Spray Coating on Contact Lenses Using Azido AnilineHydrochloride

[0170] A solution of 0.1 mg/mL azido aniline hydrochloride in methanolis given into a funnel of an airbrush (aero-pro 381™, Hansa). Thesolution is sprayed onto both sides of wet or dried Lotrafilcon A lenses(polysiloxane/perfluoroalkylpolyether copolymer) for the time asindicated in the Table below using a nitrogen pressure of 1.15 bar.Afterwards the lenses are irradiated 30 seconds using a UV lamp (LQ400B, Gröbel) with an intensity of 1.43 mW/cm² and a 305 nm cutofffilter. The whole process is optionally repeated. The lenses are thenextracted in acetonitrile/methanol 80/20 overnight. TABLE Spray time inseconds/ Lens surfaces before Example Number of spray cycles sprayingA-3 3/1 dry A-4 7/1 dry A-5 7/1 wet A-6 7/3 dry

EXAMPLE B-1 Surface Binding of the Reactive Photoinitiator Molecules

[0171] The aminofunctionalized contact lenses from Example A-1 are,immediately after plasma treatment with 1,2-DACH plasma, immersed into a1% acetonitrile solution of the reactive photoinitiator prepared by theaddition reaction from isophorone diisocyanate and4-(2-hydroxyethoxy)phenyl 2-hydroxy-2-propyl ketone (Darocure 2959)(synthesis see EP 0 632 329). The amino groups on the lenses surfacesreact with the isocyanato groups of the photoinitiator molecules for 12h. After this time, the lenses are withdrawn from the reaction solution,washed and extracted in acetonitrile for 8 h and dried under reducedpressure for 2 h. The dried lenses are subsequently used forphotografting.

EXAMPLE B-2 Surface Binding of Reactive Photoinitiator Molecules

[0172] The aminofunctionalized contact lenses from Example A-1 are,immediately after plasma treatment with 1,2-DACH plasma, immersed into a1% acetonitrile solution of the reactive photoinitiator prepared by theaddition reaction from isophorone diisocyanate and2-ethyl-2-(dimethylamino)-1-[4-(2-hydroxyethoxy)phenyl]-4-penten-1-one(synthesis see WO 96/20796). The amino groups on the lenses surfacesreact with the isocyanato groups of the photoinitiator molecules for 16h. After this time, the lenses are withdrawn from the reaction solution,washed and extracted in acetonitrile for 12 h and dried under reducedpressure for 2 h. The dried lenses are subsequently used forphotografting.

EXAMPLE B-3 Synthesis of a Reactive Photoinitiator Comprising a ReactiveAmino Group

[0173] A 1000 ml three-necked round botton flask is charged with asolution of 224.26 g (1 Mol) of Darocure 2959 in 400 ml of THF and114.55 g (1 Mol) of methanesulfonyl chloride is added to the solution atRT. After cooling to 2° C., 101.2 g (1 Mol) of triethyl amine (TEA) andadditional 200 ml of THF are added to the solution for 30 min understirring. Slightly exothermal reaction is observed. The reaction mixtureis than filtered through G3 glass frit filter and the TEA hydrochloridewashed 2× with THF on the filter. The solvent from the filtrate isevaporated at 60° C. and the pressure 200 mbar using a Rotavapor. Theyellow oil is than dissolved in 800 ml of CH₂Cl₂. The organic phase iswashed 1× with 400 ml of deionized water, 2× with 400 ml of acidic waterpH˜1 and finally with 400 ml of deionized water. The organic phase isthan dried over MgSO₄, filtered and concentrated to the constant weightby evaporating of the CH₂Cl₂ at a Rotavapor. 10.1 g of the driedcompound is than dissolved in 30 ml CH₂Cl₂. After addition of 50 g ofethanolamine, the mixture is heated to 80° C. and stirred at thistemperature for 1 h. The unreacted ethanolamine is than distilled offand the product is dissolved in 100 ml of 2 N HCl. After 20 minutes ofstirring, the

[0174] The isocyanato functionalized contact lenses from Example A-2are, immediately after plasma treatment with 2-IEM plasma, immersed into1% acetonitrile solution of the reactive photoinitiator preparedaccording to Example B-3. The isocyanate groups on the lenses surfacesreact with the amino groups of the photoinitiator molecules for 12hours. After this time, the lenses are withdrawn from the reactionsolution, washed and extracted in acetonitrile for 8 hours and driedunder reduced pressure for 2 hours. The dried lenses are subsequentlyused for photografting.

EXAMPLES B-5-B-8 Surface Binding of Reactive Photoinitiator Molecules

[0175] The aminofunctionalized contact lenses from Examples A-3-A-6 areimmersed into a 1% by weight solution of the reactive photoinitiatorprepared by the addition reaction from isophorone diisocyanate and4-(2-hydroxyethoxy)phenyl 2-hydroxy-2-propyl ketone (Darocure 2959)(synthesis see EP 0 632 329) in acetonitrile. 3 drops of triethylamine(TEA) are then added to the solution. The amino groups on the lenssurface react with the isocyanato groups of the photoinitiator moleculesfor 12 h. After this time, the lenses are withdrawn from the reactionsolution, 3× washed and extracted in acetonitrile for 8 h and driedunder reduced pressure for 2 h. The dried lenses are subsequently usedfor photografting.

EXAMPLE B-9-B-12 Surface Binding of the Reactive PhotoinitiatorMolecules

[0176] The aminofunctionalized contact lenses from Examples A-3 to A-6are dried to the constant mass under reduced pressure. The lenses arethen directly immersed into 1% by weight acetonitrile solution of thereactive photoinitiator prepared by the addition reaction fromisophorone diisocyanate and2-dimethylamino-2-benzyl-1-[4-(2-hydroxyethoxy)phenyl]-butan-1-one(synthesis see WO 96/20796 (5 ml solution/lens). 3 drops oftriethylamine (TEA) are then added to the solution. The amino groups onthe lens surface react with the isocyanato groups of the photoinitiatormolecules for 12 h. After this time, the lenses are withdrawn from thereaction solution, 3× washed and extracted in acetonitrile for 6 h anddried under reduced pressure for 2 h. The dried lenses are subsequentlyused for photografting.

EXAMPLE C-1 Acrylamide Telomer (M_(n) 1880)

[0177] A 2000 ml round bottom flask is charged with a solution of 142.1g (2 Mol) acrylamide (Fluka 01696) in 700 ml of deionized water andcooled to −5° C. The frozen solution is evacuated to 50 mbar and afterheating to RT filled with nitrogen gas. This freeze taw process isrepeated three times.

[0178] 1.1 g (4 mmol) of α,α′-azodiisobutyramidine dihydrochloride(Fluka 11633) and 17.5 g (0.154 Mol) cysteamine hydrochloride (Fluka30080) are added to the cooled solution under nitrogen atmosphere. Theclear and slightly yellowish solution is acidified with a few drops of32% hydrochloric acid to pH 3.

[0179] With a constant stream of argon, this solution is cooled to 5° C.and slowly introduced onto an ‘flow-through-reactor’ consisting of an2000 mL three-necked round-bottom flask, reflux condenser, thermometer,magnetic stirrer and a 30 cm Liebig-condenser, filled with glass wool.The Liebig condenser is heated to 70° C., the flask is heated to 60° C.The cooled solution is slowly dropped through the Liebig-condenser intothe stirred flask using the Chromatography Pump Büchi 681. This takes 1h 40 min. During this time the temperature in the flask is kept between58-65° C. After the completed addition, the solution is stirred for 2 hat 60° C.

[0180] After cooling to RT, NaOH is added to the clear and slightlyyellowish solution until pH 10.5 was reached. The product is purifiedthrough reverse osmosis, using Millipore cartridge with a cut-off at1000 Da and freeze-dried. A bright-white solid product is obtained witha yield of 87%. The concentration of amino groups is determined viafunctional group titration (6.53 mEq/g), which corresponds to M_(n) 1880Da.

EXAMPLE C-2 Acrylamide Telomer (M_(n) 1350)

[0181] A 1000 mL round bottom flask is charged with a solution of 99.5 g(1.46 mol) acrylamide (Fluka 01696), 1.27 g (4.68 mmol)α,α′-azodiisobutyramidine dihydrochloride (Fluka 11633) and 15.9 g (0.14mol) cysteamine hydrochloride (Fluka 30080) in 300 ml of water. Theclear and slightly yellowish solution is acidified with a few drops of32% hydrochloric acid to pH 3. The stirred acidic solution is evacuatedto 50 mbar and filled with argon. This is repeated three times.

[0182] With a constant stream of argon, this solution is poured into a500 ml dropping funnel which was put onto an ‘flow-through-reactor’consisting of an 1000 ml three-necked round-bottom flask, refluxcondenser, thermometer, magnetic stirrer and a 30 cm Liebig-condenser,which is filled with glass wool. The whole apparatus is constantlypurged with argon.

[0183] The dropping funnel is put onto the Liebig condenser, which isheated to 65° C. The flask is heated to 60° C. The solution is slowlydropped through the Liebig condenser into the stirred flask. This takes2 h. During this time the temperature in the flask is kept between58-65° C. After the completed addition, the solution is stirred for 2 hat 60° C. NaOH is added to the clear and slightly yellowish solutionuntil pH 10 is reached. The product is purified through reverse osmosis,using Millipore cartridge with a cut-off at 1000 Da and thenfreeze-dried for 18 h. A bright-white solid product is obtained in ayield of 77%. The concentration of amino groups is determined viafunctional group titration (0.70 mEq/g) which corresponds well with thesulfur-value of the elemental analysis (0.73 mEq/g). The correspondingnumber average molecular weight M_(n) is 1350 Da.

EXAMPLE C-3 N,N-Dimethylacrylamide Telomer (M_(n) 1850)

[0184] A 2000 ml round bottom flask is charged with a solution of 198.2g (2 mol) acrylamide (Fluka 01696), 2.72 g (10 mmol)α,α′-azodiisobutyramidine dihydrochloride (Fluka 11633) and 24.8 g (0.22mol) cysteamine hydrochloride (Fluka 30080) in 600 mL of water. Theclear and slightly yellowish solution is acidified with a few drops of32% hydrochloric acid to pH 3. The stirred acidic solution is evacuatedto 50 mbar and filled with argon. This is repeated three times.

[0185] With a constant stream of Argon, this solution is poured into a1000 mL dropping funnel which was put onto an ‘flow-through-reactor’consisting of an 1000 mL three-necked round-bottom flask, refluxcondenser, thermometer, magnetic stirrer and a 30 cm Liebig-condenser,which is filled with glass wool. The whole apparatus is constantlypurged with Argon. The dropping funnel is put onto the Liebig condenser,which is heated to 60° C. The flask was also heated to 60° C. Thesolution is slowly dropped through the Liebig-condenser into the stirredflask. This takes 2.5 h. During this time the temperature in the flaskis kept between 58-65° C. After the completed addition, the solution isstirred for 2 h at 60° C. 30% NaOH solution is added to the clear andslightly yellowish solution until pH 10 is reached. The product ispurified through reverse osmosis, using a Millipore cartridge with acut-off at 1000 Da and freeze-dried. A bright-white solid product isobtained in a yield of 75%. The concentration of amino groups isdetermined via functional group titration (0.54 mEq/g). Thecorresponding number average molecular weight M_(n) is 1850 Da.

EXAMPLE D-1 Preparation of a Macromonomer Solution

[0186] 3 g of acrylamide telomer with amino end group (aminetitration=0.70 mEq/g), prepared by Example C-2 is dissolved in 30 mL ofHPLC water. Argon is then let to bubble through the solution for theperiod of about 30 min. This mixture is then added to the equimolaramount (0.321 g) of isocyanatoethyl methacrylate (IEM, isocyanatetitration=6.45 mEq/g) under stirring. The whole mixture was then stirredunder argon flow for 12 h. After this reaction the mixture is used forsubsequent reactions.

EXAMPLE D-2 Preparation of a Macromonomer Solution Comprising SodiumHyaluronate

[0187] 10 ml of the solution from Example D-1 and 10 ml of 0.5% aqueoussolution of sodium hyaluronate (Denki Kagaku Kogyo, Mn.about.1.2×10⁻⁶Da) are mixed together and homogenized by stirring for 1 h. After addingof 0.2 g of NaCl to the solution and 10 min stirring, the mixture isfiltered through 1.2 μm Teflon filter, degassed by repeated (3×)evacuation and bubbling with argon in order to remove dissolved oxygenand used for photografting.

EXAMPLE D-3 Preparation of s Macromonomer Solution ComprisingPoly-N-Vinylpyrrolidone

[0188] 10 ml of the solution from Example D-1 and 10 ml of 1% aqueoussolution of poly-N-vinylpyrrolidone (Polysciences, Inc., Cat # 01052, Mw40000, pharmaceutical grade) are mixed together and homogenized bystirring for 1 h. After adding of 0.2 g of NaCl to the solution and 10minutes stirring, the mixture is filtered through a 0.45 μm Teflonfilter, degassed by repeated (3×) evacuation and bubbling with argon inorder to remove dissolved oxygen and used for photografting.

EXAMPLE D-4 Preparation of a Macromonomer Solution Comprising Carbopol981 NF

[0189] 10 ml of the solution from Example D-1 and 10 ml of 0.5% aqueoussolution of Carbopol 981 NF (BFGoodrich) are mixed together andhomogenized by stirring for 1 h. After adding of 0.2 g of NaCl to thesolution and 10 min stirring, the mixture is filtered through a 1.2 μmTeflon filter, degassed by repeated (3×) evacuation and bubbling withargon in order to remove dissolved oxygen and used for photografting.

EXAMPLE D-5 Preparation of a Macromonomer Solution Comprising SodiumHyaluronate

[0190] 10 ml of the solution from Example D-1 and 10 ml of 0.2% aqueoussolution of sodium hyaluronate were mixed together and homogenized bystirring for 1 h. After adding of 0.2 g of NaCl to the solution and 10min stirring, the mixture is filtered through a 1.2 μm Teflon filter,degassed by repeated (3×) evacuation and bubbling with argon in order toremove dissolved oxygen and used for photografting.

EXAMPLE D-6 Preparation of a Macromonomer Solution Comprising SodiumHyaluronate

[0191] 3 g of N,N-dimethylacrylamide telomer with amino end group (aminetitration=0.53 mEq/g), prepared by Example C-3 are dissolved in 15 ml ofHPLC water. This mixture is then added to the equimolar amount (0.25 g)of isocyanatoethyl methacrylate (IEM, isocyanate titration=6.45 mEq/g)under stirring. The whole mixture is then stirred under argon flow for12 h. After adding of 15 mL of the 0.2% aqueous solution of sodiumhyaluronate to the solution and 40 min stirring, the mixture is filteredthrough a 1.2 μm Teflon filter, degassed with nitrogen in order toremove oxygen and used for photografting.

EXAMPLE E-1 Photografting of a Macromonomer Solution Comprising SodiumHyaluronate Onto a Contact Lens Surface

[0192] In a glove box, 1 mL of the solution from Example D-2 isintroduced into a small Petri dish of a volume of about 2 mL. The lensfrom Example B-1, carrying covalently linked photoinitiator molecules onits surface, is then placed into this solution and an additional 0.5 mLof the degassed solution is added on the lens in order to cover thewhole lens with the solution. After 10 min, the Petri dish with the lensunder the solution is exposed to 14 mW ultraviolet light for a period ofabout 2 min. The lens is then turned over and the exposition is repeatedby applying 14 mW UV light for an additional 2 min.

[0193] The modified lens is then withdrawn from the solution, washed 3×in distilled water, continuously extracted in ultra pure water for 16 hand analyzed by contact angle measurements.

[0194] Water/air contact angles on the modified lens are 0° adv., 0°rec., 0° hysteresis. In comparison, the contact angles of non-modifiedlens are 101° adv., 64° rec., 37° hysteresis. The lens holds continuouswater layer on the surface for over 1 min.

EXAMPLE E-2 Photografting of a Macromonomer Solution Comprising Carbopol981 NF onto a Contact Lens Surface

[0195] 1 ml of the solution from Example D-4 is introduced into a smallPetri dish of a volume of about 2 ml in a glove box. The dried lens fromExample B-1, carrying covalently linked photoinitiator molecules on itssurface, is then placed into this solution and an additional 1 mL of thedegassed solution was added on the lens in order to cover the whole lenswith the solution. After 15 min, the Petri dish with the lens in thesolution is exposed to 14 mW ultraviolet light for a period of about 2min. The lens is then turned over and the exposition was repeated byapplying 14 mW UV light for an additional 2 min.

[0196] The modified lens is then withdrawn from the solution, washedtwice in distilled water, continuously extracted in ultra pure water for16 h and analyzed by AFM, ATR-FTIR and contact angle measurements.

[0197] The thickness of the coating is in the range of 300-400 nm asdetermined by AFM. Water/air contact angles on the modified lens are 4°adv., 0° rec., 4° hysteresis. In comparison, the contact angles ofnon-modified lens are 101° adv., 64° rec., 37° hysteresis. The lensholds continuous water layer on the surface for over 1 min.

EXAMPLE E-3 Photografting of a Macromonomer Solution ComprisingPoly-N-vinlpyrrolidone Onto a Contact Lens Surface

[0198] Two lenses from Example B-1 are coated in accordance with ExampleE-1, but instead of the solution from Example D-2, the solution fromExample D-3 is used for UV coupling. Water/air contact angles on themodified lenses are 5° adv., 0° rec., 5° hysteresis.

EXAMPLE E-4 Photografting of a Macromonomer Solution Comprising SodiumHyaluronate Onto a Contact Lens Surface

[0199] 1 ml of the solution from Example D-5 is introduced into a smallPetri dish of a volume of about 2 ml in a glove box. The dried lens fromExample B-1, carrying covalently linked photoinitiator molecules on itssurface, is then placed into this solution and an additional 1 mL of thedegassed solution is added on the lens in order to cover the whole lenswith the solution. After 15 min the Petri dish with the lens in thesolution is exposed to 15 mW ultraviolet light for a period of about 1min. The modified lens is then withdrawn from the solution, washed twicein distilled water, continuously extracted in ultra pure water for 16 hand analyzed by ATR-FTIR and contact angle measurements.

[0200] The thickness of the coating is in the range of 200-300 nm asdetermined by AFM. Water/air contact angles on the modified lens are 0°adv., 0° rec., 0° hysteresis. In comparison, the contact angles ofnon-modified lens are 101° adv., 64° rec., 37° hysteresis. The lensholds continuous water layer on the surface for over 1 min.

EXAMPLE E-5 Photografting of a Macromonomer Solution Comprising SodiumHyaluronate Onto a Contact Lens Surface

[0201] Five lenses from Example B-4 are coated in accordance withExample E-1, but instead of the solution from Example D-2, the solutionfrom Example D-5 is used for UV coupling. Water/air contact angles onthe modified lenses are 4° adv., 0° rec., 4° hysteresis.

EXAMPLE E-6 Photografting of a Macromonomer Solution Comprising SodiumHyaluronate Onto a Contact Lens Surface

[0202] Five lenses from Example B-4 are coated in accordance withExample E-5, but instead of the solution from Example D-5, the solutionfrom Example D-2 is used for UV coupling. Water/air contact angles onthe modified lenses are 0° adv., 0° rec., 0° hysteresis.

EXAMPLE E-7 Photografting of a Macromonomer Solution Comprising SodiumHyaluronate Onto a Contact Lens Surface

[0203] Five lenses from Example B-4 are coated in accordance withExample E-5, but instead of the solution from Example D-5, the solutionfrom Example D-6 is used for UV coupling. Water/air contact angles onthe modified lenses are 15° adv., 9° rec., 6° hysteresis.

1. A process for coating a biomedical device, which comprises: (a)providing an inorganic or organic bulk material having covalently boundto its surface initiator moieties for radical polymerization; (b) graftpolymerizing a hydrophilic ethylenically unsaturated macromonomer fromthe bulk material surface in the presence of a biocompatible hydrophilicpolymer being devoid of polymerizable ethylenically unsaturated groupsand thereby entrapping said hydrophilic polymer within the polymermatrix formed by the polymerization of the macromonomer.
 2. A processaccording to claim 1, wherein the material surface is the surface of abiomedical device, particularly a contact lens, intraocular lens orartificial cornea.
 3. A process according to claim 1 or 2, wherein theattachment of the initiator moieties to the bulk material comprises: (a)providing a bulk material surface with H-active groups; (b) reacting thebulk material surface with a functional polymerization initiator havinga functional group that is co-reactive to said H-active groups.
 4. Aprocess according to claim 1 or 2, wherein the attachment of theinitiator moieties to the bulk material comprises: (a) reacting thematerial surface with a compound of formula

wherein R₂₉ is C₁-C₄-alkyl, C₁-C₄-alkoxy, hydroxy, sulfo, nitro,trifluoromethyl or halogen, g is an integer from 0 to 2, L₁ is a group,which functions as a triggerable precursor for carbene or nitreneformation, L₂ is amino, C₁-C₄-alkylamino, hydroxy, glycidyl, carboxy ora derivative thereof, isocyanato or isothiocyanato, or is a radical offormula —[L₃]_(h)—(spacer)—L₂′  (1a) L₂′ is amino, C₁-C₄-alkylamino,hydroxy, carboxy or a derivative thereof, isocyanato, isothiocyanato,—O-glycidyl or —O—C(O)—(CH₂)_(h1)—X₂, wherein h1 is from 1 to 4 and X₂is carboxy or a derivative thereof, L₃ is —NH—, —NC₁—C₆-alkyl-, —O—,—C(O)O—, —C(O)NH—, —NHC(O)NH—, —NHC(O)O— or —OC(O)NH—; (spacer) islinear or branched C₁-C₂₀₀-alkylene which may be substituted by hydroxyand/or interrupted by —O— except for C₁-alkyl, or isC₃-C₈-cycloalkylene, C₃-C₈-cycloalkylene-C₁-C₆-alkylene,C₃-C₈-cycloalkylene-C₁-C₂-alkylene-C₃-C₈-cycloalkylene orC₁-C₆-alkylene-C₃-C₈-cycloalkylene-C₁-C₆-alkylene; and h is the number 0or 1; (b) reacting the so modified surface with a functionalpolymerization initiator having a functional group that is co-reactiveto L₂ or L₂′.
 5. A process according to any one of claims 1, 2 or 4,wherein step (a) comprises applying the compound of formula (1) to thematerial surface and fixing said compound of formula (1) onto thematerial surface using radiation, in particular UV or visible light. 6.A process according to any one of claims 1, 2, 4 and 5, wherein L₁ isthe radical of formula

g is 0, and L₂ is carboxy or a derivative thereof or is a radical offormula —L₃—(spacer)—L₂′, wherein L₃ is —C(O)O— or —C(O)NH—, (spacer) islinear C₂-C₁₂-alkylene or—(C₂-C₃-alkylene)—O—(CH₂CH₂O)₁₈₋₁₆₀—(C₂-C₃-alkylene)—, and L₂′ iscarboxy, a carboxy derivative or a radical —O—C(O)—(CH₂)₂—X₂, wherein X₂is carboxy or a carboxy derivative.
 7. A process according to any one ofclaims 1, 2, 4, 5 and 6, wherein L₁ is the azide radical —N₃, g is 0 or1, R₂₉ is methyl, methoxy, hydroxy or nitro, and L₂ is amino, carboxy, acarboxy derivative, isocyanato, isothiocyanato or a radical of formula—L₃—(spacer)—L₂′, wherein L₃ is —NH— —C(O)O— or —C(O)NH—, (spacer) islinear C₂-C₁₂-alkylene or—(C₂-C₃-alkylene)—O—(CH₂CH₂O)₁₈₋₁₆₀—(C₂-C₃-alkylene)—, and L₂′ iscarboxy, a carboxy derivative or a radical —O—C(O)—(CH₂)₂—X₂, wherein X₂is carboxy or a carboxy derivative.
 8. A process according to claims 3or 4, wherein the functional polymerization initiator is aphotoinitiator of formula

wherein Z is bivalent —O—, —NH— or —NR₁₂—; Z₁ is —O—, —O—(O)C—, —C(O)—O—or —O—C(O)—O—; R₃ is H, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy or N—C₁-C₁₂-alkylamino; R₄ and R₅ are each independently of the other H, linearor branched C₁-C₈-alkyl, C₁-C₈-hydroxyalkyl or C₆-C₁₀-aryl, or thegroups R₄—(O)_(b1)— and R₄—(O)_(b2)— together are —(CH₂)_(c)— wherein cis an integer from 3 to 5, or the groups R₄—(O)_(b1)—, R₄—(O)b₂— andR₅—(O₁)b₃— together are a radical of the formula

R₂ is a direct bond or linear or branched C₁-C₈-alkylene that isunsubstituted or substituted by —OH and/or is uninterrupted orinterrupted by one or more groups —O—, —O—C(O)— or —O—C(O)—O—; R₁ isbranched C₃-C₁₈-alkylene, unsubstituted or C₁-C₄-alkyl— orC₁-C₄-alkoxy-substituted C₆-C₁₀-arylene, or unsubstituted orC₁-C₄-alkyl- or C₁-C₄-alkoxy-substituted C₇-C₁₈-aralkylene,unsubstituted or C₁-C₄-alkyl- or C₁-C₄-alkoxy-substitutedC₃-C₈-cycloalkylene, unsubstituted or C₁-C₄-alkyl- orC₁-C₄-alkoxy-substituted C₃-C₈-cyclo-alkylene-C_(y)H_(2y)— orunsubstituted or C₁-C₄-alkyl- or C₁-C₄-alkoxy-substituted—C_(y)H_(2y)—(C₃-C₈-cycloalkylene)—C_(y)H_(2y)— wherein y is an integerfrom 1 to 6; R₆ independently has the same definitions as R₁ or islinear C₃-C₁₈-alkylene; R₁₂ is linear or branched C₁-C₆-alkyl; T isbivalent —O—, —NH—, —S—, C₁-C₈-alkylene or

Z₂ is a direct bond or —O—(CH₂)_(d)— or —(OCH₂CH₂)_(d)— wherein d is aninteger from 1 to 6 and the terminal CH₂ group of which is each linkedto the adjacent T in formula (3c); R₈ is linear or branched C₁-C₈-alkyl,C₂-C₈-alkenyl or C₆-C₁₀-aryl-C₁-C₈-alkyl; R₉ independently of R₈ has thesame definitions as R₈ or is C₆-C₁₀-aryl, or R₈ and R₉ together are—(CH₂)_(e)— wherein e is an integer from 2 to 6; R₁₀ and R₁₁ are eachindependently of the other linear or branched C₁-C₈-alkyl that may besubstituted by C₁-C₄-alkoxy, or C₆-C₁₀-aryl-C₁-C₈-alkyl orC₂-C₈-alkenyl; or R₁₀ and R₁₁ together are —(CH₂)_(f1)—Z₃—(CH₂)_(f2)—wherein Z₃ is a direct bond, —O—, —S— or —NR₇—, and R₇ is H orC₁-C₈-alkyl and f1 and f2 are each independently of the other an integerfrom 2 to 4; R₁₃ and R₁₃′ are each independently of the other H,C₁-C₈-alkyl, C₃-C₈-cycloalkyl, benzyl or phenyl; and a, a1, b1, b2 andb3 are each independently of the other 0 or 1; subject to the provisosthat b1 and b2 are each 0 when R₁₅ is H; that the total of (b1+b2+b3) isnot exceeding 2; and that a is 0 when R₁₂ is a direct bond.
 9. A processaccording to any one of claims 1 to 8, wherein a macromonomer of formula

is applied in step (b), wherein R₃₂ is hydrogen, C₁-C₆-alkyl or aradical —COOR′; R, R′ and R₃₂′ are each independently of the otherhydrogen or C₁-C₆-alkyl; A is a direct bond or is a radical of formula—C(O)—(A₁)_(n)—X—  (5a) or —(A₂)_(m)—NH—C(O)—X—  (5b) or—(A₂)_(m)—X—C(O)—  (5c) or —C(O)—NH—C(O)—X—  (5d) or—C(O)—X₁—(alk*)—X—C(O)—  (5e) or A and R₃₂, together with the adjacentdouble bond, are a radical of formula

A₁ is —O—C₂-C₁₂-alkylene which is unsubstituted or substituted byhydroxy, or is —O—C₂-C₁₂-alkylene—NH—C(O)— or—O—C₂-C₁₂-alkylene-O—C(O)—NH—R₃₃—NH—C(O)— or —NH—(Alk*)—C(O)—, wherein(Alk*) is C₁-C₆-alkylene and R₃₃ is linear or branched C₁-C₁₈-alkyleneor unsubstituted or C₁-C₄-alkyl- or C₁-C₄-alkoxy-substitutedC₆-C₁₀-arylene, C₇-C₁₈-aralkylene,C₆-C₁₀-arylene-C₁-C₂-alkylene-C₆-C₁₀-arylene, C₃-C₈-cycloalkylene,C₃-C₈-cycloalkylene-C₁-C₆-alkylene,C₃-C₈-cycloalkylene-C₁-C₂-alkylene-C₃-C₈-cycloalkylene orC₁-C₆-alkylene-C₃-C₈-cycloalkylene-C₁-C₆-alkylene; A₂ is C₁-C₈-alkylene;phenylene or benzylene; m and n are each independently of the other thenumber 0 or 1; X, X₁ and X′ are each independently of the other abivalent group —O— or —NR″, wherein R″ is hydrogen or C₁-C₆-alkyl;(alk*) is C₂-C₁₂-alkylene; and (oligomer) denotes (i) the radical of atelomer of formula

wherein (alk) is C₂-C₁₂-alkylene, Q is a monovalent group that issuitable to act as a polymerization chain-reaction terminator, p and qare each independently of another an integer from 0 to 350, wherein thetotal of (p+q) is an integer from 2 to 350, and B and B′ are eachindependently of the other a 1,2-ethylene radical derivable from acopolymerizable vinyl monomer by replacing the vinylic double bond by asingle bond, at least one of the radicals B and B′ being substituted bya hydrophilic substituent; or (ii) the radical of an oligomer of theformula

wherein R₁₉ is hydrogen or unsubstituted or hydroxy-substitutedC₁-C₁₂-alkyl, u is an integer from 2 to 250 and Q′ is a radical of apolymerization initiator; or (iii) the radical of formula

wherein R₁₉, X and u are as defined above, or (iv) the radical of anoligomer of formula

wherein R₂₀ and R₂₀′ are each independently C₁-C₄-alkyl, An⁻is an anion,v is an integer from 2 to 250, and Q″ is a monovalent group that issuitable to act as a polymerization chain-reaction terminator; or (v)the radical of an oligopeptide of formula—(CHR₂₁—C(O)—NH)_(t)—CHR₂₁—COOH  (6d) or —CHR₂₁—(NH—C(O)—CHR₂₁)_(t)—NH₂  (6d′) wherein R₂₁ is hydrogen or C₁-C₄-alkyl which is unsubstituted orsubstituted by hydroxy, carboxy, carbamoyl, amino, phenyl, o- , m-0 orp-hydroxyphenyl, imidazolyl, indolyl or a radical —NH—C(═NH)—NH₂ and tis an integer from 2 to 250, or the radical of an oligopeptide based onproline or hydroxyproline; or (vi) the radical of a polyalkylene oxideof formula—(alk^(**)—O)_(z)—[CH₂—CH₂—O]_(r)—[CH₂—CH(CH₃)—O]_(s)—R₃₄  (6e) whereinR₃₄ is hydrogen or C₁-C₂₄-alkyl, (alk^(**)) is C₂-C₄-alkylene, z is 0 or1, r and s are each independently an integer from 0 to 250 and the totalof (r+s) is from 2 to 250; or (vii) the radical of an oligosaccharide;subject to the provisos that A is not a direct bond if (oligomer) is aradical of formula (6a); A is a radical of formula (5a), (5b) or (5d) orA and R₃₂, together with the adjacent double bond, are a radical offormula (5f) if (oligomer) is a radical of formula (6b), (6c), (6d) or(6e) or is the radical of an oligosaccharide; A is a direct bond if(oligomer) is a radical of formula (6b′); and A is a radical of formula(5c) or (5e) if (oligomer) is a radical of formula (6d′).
 10. A processaccording to claim 9, wherein R is hydrogen or methyl, R₃₂ and R₃₂′ areeach hydrogen, A is a radical of the formula (5a) and (oligomer) is aradical of formula (6a).
 11. A process according to claim 9 or 10,wherein (oligomer) is a radical of formula

wherein (alk) is C₂-C₄-alkylene, R₂₅ and R₂₅′ are each independentlyhydrogen or methyl, Q is a monovalent group that is suitable to act as apolymerization chain-reaction terminator, p and q are each independentlyan integer from 0 to 100 wherein the total of (p+q) is an integer from 5to 100, and R₂₆ and R₂₆′, are each independently a radical —COOY,wherein Y is C₁-C₂-alkyl, C₂-C₃-alkyl, which is substituted by hydroxy,amino or N,N-di-C₁-C₂-alkyl-amino, or is a radical-C₂-C₄-alkylene-NH—C(O)—O—G wherein —Q—G is the radical of trehalose; aradical —CO—NY₁Y₂, wherein Y₁ and Y₂ are each independently of the otherhydrogen or C₁-C₂-alkyl which is unsubstituted or substituted byhydroxy, or Y₁ and Y₂ together with the adjacent N-atom form aN—C₁-C₂-alkylpiperazino or morpholino ring; a heterocyclic radicalselected from the group consisting of N-pyrrolidonyl, 2- or 4-pyridinyl,2-methylpyridin-5-yl, 2-3- oder 4-hydroxypyridinyl, N-ε-caprolactamyl,N-imidazolyl, 2-methylimidazol-1-yl, N-morpholinyl and4-N-methylpiperazin-1-yl; —COOH; —SO₃H; o-, m- or p-sulfophenyl; o-, m-or p-sulfomethylphenyl; a radical —CONY₅Y₆ wherein Y₅ is C₂-C₄-alkylsubstituted by sulfo, and Y₆ is hydrogen; C₁-C₄-alkyl which issubstituted by —NR₂₃R₂₃′R₂₃″⁺An⁻ wherein R₂₃, R₂₃′ and R₂₃″ are eachindependently of another hydrogen or C₁-C₄-alkyl and An⁻ is an anion; aradical —C(O)OY₇ wherein Y₇ is C₂-C₄-alkyl, which is substituted by—NR₂₃R₂₃′R₂₃″⁺An⁻ and is further unsubstituted or substituted byhydroxy, wherein R₂₃, R₂₃′, R₂₃″ and ⁺An⁻ are as defined; and a radical—C(O)O—CH₂—CH(OY₈)—CH₂—O—PO₂ ⁻—(CH₂)₂—N(CH₃)₃ ⁺, wherein Y₈ is hydrogenor the acyl radical of a higher fatty acid.
 12. A process according toany one of claims 1 to 11, wherein in step (b) a macromonomer of formula

is applied, wherein R is hydrogen or methyl, (alk) is C₂-C₄-alkylene,R₂₅ is hydrogen or methyl, p is an integer of 5 to 50, Q is a monovalentgroup that is suitable to act as a polymerization chain-reactionterminator, and R₂₆ is a radical —CONH₂, —CON(CH₃)₂ or


13. A process according to any one of claims 1 to 12, wherein thebiocompatible hydrophilic polymer applied in step (b) is selected fromthe group consisting of hyaluronic acid, chondriotin sulfate, heparin,dextran and mucin.
 14. A process according to any one of claims 1 to 12,wherein the biocompatible hydrophilic polymer applied in step (b) isselected from the group consisting of carboxymethylcellulose,carboxyalkylchitin and carboxyalkylchitosan.
 15. A process according toany one of claims 1 to 12, wherein the biocompatible hydrophilic polymerapplied in step (b) is selected from the group consisting of apolyoxyalkylene amine, polyethylene glycol, poly-HEMA, a crosslinkedpolyacrylic acid based polymer, polyacrylamide, polyvinylpyrrolidone andpolyvinyalcohol.
 16. A process according to claim 1, wherein in step (b)an additional bioactive compound, for example, a polyquat, is added. 17.A composite material obtainable by the process of any one of claims 1 to16.
 18. A composite material according to claim 17, which is abiomedical device, preferably an ophthalmic device such as a contactlens, intraocular lens or artificial cornea.
 19. Use of a compositematerial according to claim 17 for the manufacture of an ophthalmicdevice, particularly for the manufacture of a contact lens, intraocularlens or artificial cornea.